Amyotrophic Lateral Sclerosis (ALS) is a fatal disease of unknown origin without effective treatment identified so far. The metaboreflex is activated by skeletal muscles during physical exercise to meet the raised demand for oxygen in energy production. With increased activity of the mitochondrial respiratory chain, uncoupling proteins counteract the risk presented by the generated harmful reactive oxygen species but at the expense of energy generation. The enhanced metaboreflex with raised sympathetic nervous system activity, and the enhanced uncoupling may explain motoneuron degeneration and muscle wasting, which are the main symptoms in ALS. Here it is proposed that dysregulation of the metaboreflex, maintained by mitochondrial respiratory chain uncoupling, initiate a vicious circle that account for the pathogenesis of ALS. Thus, this publication comments on a potential insight that may inform the search for effective therapy.
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